1. Field of the Invention
The present invention is in the field of compositions and methods for reducing serum glucose and triglyceride levels in diabetic mammals. More particularly, the present invention relates to treatment of diabetic mammals with compositions containing one or more compounds that are significantly more efficacious as agonists toward RXRβ receptors than toward RXRα and RXRγ retinoid receptors, without the treatment causing a reduction of serum thyroxine levels and transiently raising triglyceride levels. The present invention also relates to novel compounds of selective efficacy as agonists of RXRβ receptors and to a method of identifying compounds suitable for reducing serum glucose and/or triglyceride levels in diabetic mammals.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARα, RARβ and RARγ, in RXR the subtypes are: RXRα, RXRβ and RXRγ. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property.
As is well known in the art of medicinal chemistry, pharmacology and related biological arts efficacy and potency of a drug are related but nevertheless different concepts. As is known the effect of a drug on an enzyme, receptor or other biological test model can be expressed in terms of results accomplished, such as, for example, the percentage of inhibition of an enzyme, or the activity attained on a receptor. IC50 numbers express a concentration at which a drug inhibits 50% of the enzyme's activity. EC50 numbers express concentration of the drug at which the drugs causes 50% activation of a receptor, the percentage of activity in this case being measured relative to a reference drug or agent which is considered to cause 100% of activity of the receptor. The smaller are the IC50 or EC50 numbers, thus showing concentrations at 50% activity, the more potent is considered the drug. Unlike potency, efficacy of a drug is not measured by the concentration at which the drug can cause 50% of an effect, but rather on the maximum effect that the drug can bring about at maximum concentration as compared to a standard compound determined to have fall efficacy. Thus, when comparing two drugs, the first one may have a lesser IC50 or EC50 concentration in a given assay, but the first drug's maximum activity even at maximum concentration may be less than the maximum activity attained by the second drug. In such a case the first drug is considered more potent, but the second one more efficacious. Two drugs may also have substantially equal potency, but substantially different efficacy, and vica versa.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319–349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324–356. For a disclosure of compounds having some structural relevance to the specific novel compounds utilized in the methods of the present invention see U.S. Pat. No. 5,801,253, and the PCT Publications WO 01/19770 and WO 97/12853.
Relatively recently it has become known that certain retinoid compounds are capable of reducing serum glucose levels in diabetic mammals. Mukherjee, R.; Davies, P. J.; Crombie, D. L. Bishoff, E. D.; Cesario, R. M.; Jow Hamann, L. G.; Boehm, M. F.; Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R. Jr.; Heyman, R. A. Sensitization of Diabetic and Obese Mice to Insulin by Retinoid X Receptor Agonists. Nature 1997, 386 (6623), 407–410. The compound (2E,4E,1′S,2′S)-3-methyl-5-[2′-methyl-2′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4dienoic acid, described in U.S. Pat. No. 6,114,533, has this property. A disadvantage of the prior art retinoid compounds that reduce serum glucose levels is that their administration usually also results in the pharmacologically undesirable reduction of serum thyroxine levels and a transient increase in serum triglyceride levels. The present invention is directed to novel compounds and methods of identifying them, where the compounds do not have these undesirable side effects.